Originally identified as endothelial-derived factors, nitric oxide (NO) and endothelin-1 (ET-1) are now known to be key mediators in a number of physiological and pathophysiological processes related to both vascular and non-vascular functions. NO is well-established as an important vasodilator but also appears to modulate a variety of functions including inflammation, neurotransmission, cell growth and proliferation, and epithelial transport. The latter includes inhibition of Na reabsorption in the collecting duct of the kidney. While ET-1 is a powerful vasoconstrictor, it too, functions as a mitogen, influences cardiac contractility, and also may serve to influence renal tubular function as a natriuretic agent. Although present in abundant quantities within renal epithelia, very little is known about the circumstances in which NO and ET-1 may influence tubular function. We hypothesize that an autocrine or paracrine feedback loop exists between NO and ET-1 production within the inner medullary collecting duct and vasa recta system. Furthermore, in experimental models of renal dysfunction such as DOCA-salt hypertension, the activity of ET-1 and NO may be increased to promote Na excretion. The overall goal of the proposed studies is to determine the interaction between NO and ET-1 in the collecting duct of the kidney. We propose that ET-1 plays an essential role in stimulating renal NO production within the collecting duct in response to increased salt load. Similar to mechanisms that occur in vascular endothelial cells, we predict that stimulation of ETB receptors in the collecting duct cells will increase NOS activity and subsequent production of NO. The specific aims of this proposal are as follows: 1. To test the hypothesis that ETB receptors mediate physiological changes in Na excretion via NO production. 2. To determine the mechanism of ET-1-mediated NO production in the collecting duct. 3. To determine the mechanism of DOCA salt-mediated pathophysiological changes in NO production.